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L0301P59 - Innate Immune System
__TOC__ Microbial Targets of the Innate Immune System *innate immune cells recognise structures that may be shared by different microbes **cells have receptors for these structures **∴ the structures exist on the pathogen but not on the mammalian cells *known as pathogen associated molecular patterns (PAMPs) Examples of PAMPs *surface structures **lipopolysaccharide (LPS) on gram negative bacteria *sugar residues **terminal mannose residues on glycoproteins feature on some bacteria *double stranded RNA **feature of many viruses *unmethylated CpG nucleotides **feature of bacterial DNA Pattern Recognition Receptors *detect the PAMPs *binding to different receptors will result in different cascade of immune events Cellular Location *extracellular on the membrane **toll-like receptors (TLR) **more likely to recognise bacteria *intracellular in the cytosol **NOD-like receptors (NLR) **RIG-like receptors (RLR) *inside the endosomal membrane **TLR receptors **more likely to recognise viruses Toll-like Receptors Types *ss = single stranded *ds = double stranded *different receptors are triggered by different PAMPs  Signalling #TLR-4 detects the bacteria and is triggered #signal transduces through the TIR domain #adaptor proteins are activated to bind and cause activation of transcription factors #leads to three possible pathways: *acute inflammation *switching on of adaptive immunity *antiviral state Activation of the Inflammasome *is a fail-safe mechanism requiring two pathways to be activated Process #NLRP-3 (sensor) is stimulated by: ##bacterial products, ##crystals, ##K+ efflux, or ##reactive oxygen species #NLRP-3 binds with an adaptor and inactive caspase-1 to form NLRP-3 inflammasome #simultaneously, PAMPs induce synthesis of inactive cytokine pro-IL1β #inactive caspase-1 is cleaved from the inflammasome and becomes activated #presence of active caspase-1 converts pro-IL1β into active IL-1β #IL-1β is secreted and induces acute inflammation Macrophages Differentiation *bone marrow stem cell —> blood monocyte —> tissue macrophage *monocyte has a smoother surface than the macrophage *several types of macrophages (depending on their location): **microglia (CNS) **Kupffer cells (liver) **alveolar macrophages (lung) **osteoclasts (bone) Activation Multiple Methods *microbe recognised by TLR transduces a signal leading to the expression of cytokines and results in inflammation *complement receptor binds to complement fragment (C3b) on microbe and will phagocytose it when activated by C5a *cytokines (gamma interferon IFN-��) produced by other cells bind to cytokine receptors and activate the macrophage to produce toxic substances to kill the microbe, includes: **reactive oxygen species (ROS) **nitric oxide (NO) Inflammatory and Anti-inflammatory *two types of macrophages **classical activated (M1) ***triggered by microbial TLR-ligand binding or presence of IFN-�� **alternatively activated (M2) ***triggered by IL-13 and IL-14 ***allow for the healing process to occur Leukocyte Migration *also known as extravasation, diapedesis *movement out of the circulatory system and into the site of tissue damage or infection Step 1: Chemo-attraction *macrophages in affected tissue release cytokines after recognition of pathogen *cytokines (TNFa, IL-1, C5a) cause endothelial cells to express selectin *circulating leukocytes are then attracted to the site due to chemotaxis **follows the chemokine gradient and aggregate where the concentration is greatest (site of infection) Step 2: Rolling Adhesion *selectin ligands located on circulating leukocytes bind to the selection molecules on the endothelial cells *binding is only loosely adhesive and results in leukocytes slowing down and rolling along the inner surface of the vessel wall Step 3: Tight Adhesion *chemokines released by macrophages activate the rolling leukocytes *causes integrin molecules, located on the leukocytes to switch from a default low-affinity state to a high-affinity state *thus integrin is able to bind strongly to the integrin ligand on the endothelial cells *results in strong adhesion and the leukocytes no longer "roll" Step 4: Endothelial Transmigration *cytoskeletons of the leukocytes reorganise so that they can spread out over the endothelial cells *leukocytes move through the endothelial layer into the site of infection Phagocytosis *used to describe the recognition and ingestion of microbes by phagocytes *phagocytes: neutrophils, macrophages, dendritic cells Process #phagocyte extends its plasma membrane around the microbe, enclosing it to form a phagosome #phagosomes fuse with lysosomes to produce phagolysosomes in which the pathogen will be destroyed #phagosome is activated to switch on a number of destructive enzymes *oxidase - converts oxygen to superoxide and oxygen radicals *inducible nitric oxide synthase - produces nitric oxide *lysosomal proteases - attack microbial proteins   Innate Cytokine Functions *production of cytokines induce inflammation, activate other immune cells and shape the nature of the adaptive immune responses Natural Killer Cell Function *directly kill virally infected or cancer cells *be “licensed” to kill phagocytosed microbes after activation by IL-12 which is secreted by the macrophage with phagocytosed microbes Activation *MHC Class I markers are found on all normal cells and help differentiate self from non-self *virally infected cells or cancer cells can have changes in MHC Class I markers *absence of normal MHC Class I markers are determined as “non-self” and destroyed Type I Interferons (IFN) *synthesis is activated when TLR engagement by bacterial or viral molecules occurs *prevents spread of virus around cells Antiviral Action *virally infected cells secrete Type IFN which bind to IFN receptors on uninfected cells *IFNs induce expression of enzymes that block viral replication by: *phosphorylate translation initiation factor = inhibit protein synthesis *produce RNAase = degrade viral RNA *inhibit viral gene expression and vision assembly